Compounds useful for treating allergic or inflammatory diseases

ABSTRACT

Novel cyclohexanes of Formulas (I) and (II) ##STR1## are described herein. They inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production; these compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase V.

This application is a National Stage application of PCT/US93/02325 filedMar. 12, 1993, now WO 93/19750, published Oct. 14, 1993, which is acontinuation-in-part of PCT/US93/02045 filed Mar. 5, 1993, nowabandoned, which is a continuation-in-part of U.S. application07/968,753, filed Oct. 30, 1992, now abandoned, which is acontinuation-in-part of U.S. application 07/862,083, filed Apr. 2, 1992,now abandoned.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing these compounds, and their use in treatingallergic and inflammatory diseases and for inhibiting the production ofTumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated inactivated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. [See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164;389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35, (10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214, 1990].

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formulas (I) and (II)as shown below, useful in the mediation or inhibition of the enzymaticactivity (or catalytic activity) of phosphodiesterase IV (PDE IV). Thesecompounds also have Tumor Necrosis Factor (TNF) inhibitory activity.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formulas (I) or (II) and a pharmaceuticallyacceptable carrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I) or (II) asshown below.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I) or (II).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (I) or (II).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (I) or (II). This method may be used for theprophylactic treatment or prevention of certain TNF mediated diseasestates amenable thereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (I) or (II).

Compounds of Formula (I) or (II) are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

In addition, compounds of Formula (I) or (II) are also useful intreating yeast and fungal infections, where such yeast and fungi aresensitive to upregulation by TNF or will elicit TNF production in vivo.

Certain novel compounds of this invention are represented by Formula(I): ##STR2##

wherein:

R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R_(5l) )_(r) R₆wherein the alkyl moieties may be optionally substituted with one ormore halogens;

m is 0 to 2;

n is 1 to 4;

r is 1 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrotheinyl, theinyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and is 0, then R₆ is other than H in --(CR₄ R₅)_(n) O(CR₄R₅)_(m) R₆ ;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m) ;

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, CH₂NHC(O)C(O)NH₂, --CH═CR_(8') R_(8'), cyclopropyl optionally substitutedby R_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H, C(O)OR₈,C(O)NR₈ R₁₀, or C.tbd.CR_(8') ;

Z' is O, NR₉, NOR₈, NCN, C(--CN)₂, CR₈ CN, CR₈ NO₂, CR₈ C(O)OR₈, CR₈C(O)NR₈ R₈, C(--CN)NO₂, C(--CN)C(O)OR₉, or C(--CN)C(O)NR₈ R₈ ;

Z is O, NR₇, NCR₄ R₅ C₂₋₆ alkenyl, NOR₁₄, NOR₁₅, NOCR₄ R₅ C₂₋₆ alkenyl,NNR₄ R₁₄, NR₄ R₁₅, NCN, NNR₈ C(O)NR₈ R₁₄, NNR₈ C(S)NR₈ R₁₄, or ═Z is2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthiolketal, 2-(1,3-dioxolane), 2(1,3-dioxane), 2-(1,3-oxathiolane), dimethylketal or diethyl ketal;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, --F, --Br, --Cl,--NO₂, --Si(R₄)₃, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈, --OR₈, --CN,--C(O)NR₁₀ R₁₁, --OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂R₉, --S(O)_(m) 'R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀,thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4-or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R₈ is independently selected from hydrogen or R₉ ;

FIG. 8' is R₈ or fluorine;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorides;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₄ R₁₄, S(O)₂ R₇, or S(O)₂ NR₄ R₁₄ ; provided that;

(f) when Z is O, X is YR₂, Y is oxygen, X₂ is oxygen, X₃ is hydrogen, sis 0, R₂ is CH₃, and R₁ is CH₃, then R₃ is other than CN;

(g) when Z is O, X₂ is oxygen, X₃ is hydrogen, s is 0, and X is YR₂,then R₃ is other than hydrogen;

(h) when Z is N-O--CH₂ CH═CH₂, X is YR₂, Y is oxygen, X₂ is oxygen, X₃is hydrogen, s is 0, R₂ is CH₃, and R₁ is CH₃, then R₃ is other than CN;

(i) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

(j) when Z is O or ═Z is 2-(1,3-dioxolane) and R₃ is CH₃, CH₂ OH or CH₂OC₁₋₄ alkyl then R₁ X₂ is not C₁ -C₃ alkoxy and X is not halogen,methoxy, ethoxy, methylthio, or ethylthio;

or the pharmaceutically acceptable salts thereof.

Another set of compounds of this invention are represented by Formula(II) ##STR3##

wherein:

R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆wherein the alkyl moieties may be optionally substituted with one ormore halogens;

m is 0 to 2;

n is 1 to 4;

r is 1 to 6;

R₄ and R₅ are independently selected hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties is unsubstitutedor substituted by 1 to 3 methyl groups or one ethyl groups;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m) ;

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, --CH═CR_(8') R_(8'), cyclopropyl optionally substituted byR_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H, C(O)OR₈, C(O)NR₈R₁₀, or C.tbd.CR_(8') ;

Z' is O, NR₉, NOR₈, NNR₈ R₈, NCN, C(--CN)₂, CR₈ CN, CR₈ NO₂, CR₈C(O)OR₉, CR₈ C(O)NR₈ R₈, C(--CN)NO₂, C(--CN)C(O)OR₉, or C(--CN)C(O)NR₈R₈ ;

R" is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN,C(NOR₈)R₁₄, C(O)NR₈ NR₈ C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)₄ 8,C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈ C(NCN)NR₁₀ R₁₄, CNCN)SR₉, (2-, 4- or5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3-or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4-or 5-isoxazolyl), (3- or 5 -oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]),(2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or5-imidazolidinyl); wherein all of there heterocyclic ring systems may beoptionally substituted one or more times by R₁₄ ;

Y' is O or S;

the remaining the substituents for compounds of Formula (II), includingR₇, q, R₁₂, R₈, R_(8'), R₉, R₁₀, R₁₁, R₁₃, R₁₄, and R₁₅ have the samedefinitions given in regards to Formula (I), where applicable;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

g) when Z" is C(O)OR₁₄ where R₁₄ is lower alkyl and R₃ is CN, then R₁ X₂is not C₁ -C₃ alkoxy and X is not halogen, methoxy, ethoxy, methylthio,or ethylthio;

or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (I) or (II).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including:asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of Formula (I) or (II). Such viruses include, but are notlimited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza,adenovirus and the Herpes group of viruses, such as, but not limited to,Herpes zoster and Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I) or (II).

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfunal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) or (II) may be administered in conjunction withother drugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin Bandliposomal Amphotericin B.

The compounds of Formula (I) or (II) may also be used for inhibitingand/or reducing the toxicity of an anti-fungal, anti-bacterial oranti-viral agent by administering an effective amount of a compound ofFormula (I) or (II) to a mammal in need of such treatment. Preferably, acompound of Formula (I) or (II) is administered for inhibiting orreducing the toxicity of the Amphotericin class of compounds, inparticular Amphotericin B.

Preferred compounds are as follows:

When R₁ for the compounds of Formula (I) or (II) is an alkyl substitutedby 1 or more halogens, the halogens are preferably fluorine andchlorine, more preferably a C₁₋₄ alkyl substituted by 1 or morefluorines. The preferred halo-substituted alkyl chain length is one ortwo carbons, and most preferred are the moieties --CF₃, --CH₂ F, --CHF₂,--CF₂ CHF₂, --CH₂ CF₃, and --CH₂ CHF₂. Preferred R₁ substituents for thecompounds of Formula (I) are CH₂ -cyclopropyl, CH₂ -C₅₋₆ cycloalkyl,C₄₋₆ cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopropyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl optionally substituted by 1or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃ O(CH₂)₀₋₂CH₃, and --(CH₂)₂₋₄ OH.

When the R₁ term is (CR_(4l) R₅), the R₄ and R₅ terms are independentlyhydrogen or alkyl. This allows for branching of the individual methyleneunits as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; each repeating methylene unit isindependent of the other, e.g., (CR₄ R₅)_(n) wherein n is 2 can be --CH₂CH(--CH₃)--, for instance. The individual hydrogen atoms of therepeating methylene unit or the branching hydrocarbon can optionally besubstituted by fluorine independent of each other to yield, forinstance, the preferred R₁ substitutions, as noted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricylco[5.2.1.0²,6 ]decyl,etc. additional examples of which are described in Saccamanao et al., WO87/06576, published 5 Nov. 1987, whose disclosure is incorporated hereinby reference in its entirely.

Preferred Z terms are O, NCN, NR₇, NOR₁₄, NOR₁₅, NNR₄ R₁₄, NNR₄,R₁₅,dimethyl ketal or dimethylthio ketal. More preferred are O or NOH.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkyloptionally substituted by 1 or more halogens. The halogen atoms arepreferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a --CF₃,--CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and --CH₃moieties.

Preferred R₃ moieties are C(O)NH₂, C.tbd.CR₈, CN, C(Z')H, CH₂ OH, CH₂ F,CF₂ H, and CF₃. More preferred are C.tbd.CH and CN. Z' is preferably Oor NOR₈. Preferred R₇ moieties include optionally substituted --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl),--(CH₂)₀₋₂ (cyclohexyl), --(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), (CH₂)₁₋₂(2-imidazolyl), (CH₂)₂ (4-morpholinyl), (CH₂)₄ -(4-piperazinyl),(CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂ (4-thiazolyl), and (CH₂)₀₋₂ phenyl;

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₈ and R₁₄ in the moiety --NR₈ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but is not limited to2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl, 5-(R₇-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5 -(R₇)-2-tetrazolyl. Applicablenitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₈ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4-or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-thiazolyl), (2-, 4-, or5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or5-imidazolidinyl).

When the R₇ group is optionally substituted by a heterocyclic ring suchas imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be optionally substituted by R₈ either onan available nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazolyl, or1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one ormore times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ --C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl,(3- or 4-cyclopentenyl), benzyl or --C₁₋₂ alkyloptionally substituted by 1 or more fluorines, and --(CH₂)₂₋₄ OH; R₂ ismethyl or fluoro-substituted alkyl, R₃ is CN or C.tbd.CR₈ ; and X isYR₂.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, methyl or CF₂ H; R₃ is CN or C.tbd.CH; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl.

A preferred subgenus of Formula (I) are the compounds of Formula (Ia)##STR4##

wherein:

R₁ is CH₂ -cyclopropyl, CH₂)₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl, C₇₋₁₁polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl,benzyl or C₁₋₂ alkyl optionally substituted by 1 or more fluorines,--(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH_(3l) , --(CH₂)₁₋₃ O(CH_(2l) )₀₋₂ CH₃, and--(CH₂)₂₋₄ OH;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1 or 2;

R₂ is --CH₃ or --CH₂ CH₃ optionally substituted by 1 or more halogens;

R₃ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl CH₂ C(O)C(O)N,CH₂ NHC(O)C(O)NH₂, CN, CH₂ OR₈, C(Z')H, C(O)OR₈, C(O)NR₈ R₁₀, orC.tbd.CR₈ ;

Z' is O or NOR₈ ;

Z is O, NR₇, NOR₁₄, NOR₁₅, NNR₄ R₁₄, NNR₄ R₁₅, NCN, or ═Z is2-(1,3-dithiane), dimethylthio ketal, 2-(1,3-dioxolane), or dimethylketal;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, --F, --BR, --Cl,--NO₂, --Si(R₄)₃, --NR₁₀ R₁₁, --C(O)R₈, --CO₂ R₈, --OR₈, --CN,--C(O)NR₁₀ R₁₁, --OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀R₁₁, --C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂R₉, --S(O)_(m') R₉, --NR₁₀ CO)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀,thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl),piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), orphenyl;

R₈ is independently selected from hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₈ and R₁₄ are as NR₈ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₄ R₁₄, S(O)₂ R₇, or S(O)₂ NR₄ R₁₄ ;

provided that:

A) when Z is O, X is YR₂, Y is oxygen, R₂ is CH₃, and R₁ is CH₃, then R₃is other than CN;

b) when R₁₂ is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN-morpholinyl, then q is not 1;

or the pharmaceutically acceptable salts thereof.

Exemplified preferred compounds of Formula (I) are:

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;

4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one;

4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexane-1-one;

4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;

4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one;

4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one;

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one oxime;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one;

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethylketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethylketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one-dimethylketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-onedimethyl ketal;

4-aminocarbonyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;

4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-onedimethyl ketal;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethylcyclohexan-1-one;

4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohex-1-one dimethylketal;

4-(3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one;

4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one dimethyl ketal;

4-(3,4-bisdifuloromethoxyphenyl)-4-formylcyclohexan-1-one dimethylketal;

4-(3,4-bisdifluoromethoxy)-4-ethynylcyclohex-1-one dimethyl ketal;

4-(3,4-bisdifluoromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-one;

4-aminomethyl-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethylketal;

4-(3,4-bisdifuloromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-onedimethyl ketal;

4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-one;

4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-oneoxime;

4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-4-ethynylcyclohexan-1-one;

4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one oxime.

Preferred Z" groups are for compounds of the Formula (II) are C(O)R₁₄,C(O)OR₁₄, C(O)NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈ R₁₄, C(O)NR₈ NR₈C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈,C(NCN)NR₁₀ R₁₄, C(NCN)SR₉, (1-, 4- or 5-[R₁₄ ]-2-imidazolyl), (1-, 4- or5-[R₁₄ ]-3-pyrazolyl), (1-, 2- or 5[R₁₄ ]-4-triazolyl[1,2,3]), (1-, 2-,4- or 5-{R₁₄ }-3-triazolyl[1,2,4]), (1- or 2-{R₁₄ }-5-tetrazolyl), (4-or 5-{R₁₄ }-2-oxazolyl), (3- or 4-{R₁₄ }-5-isoxazolyl), (3-{R₁₄ }-5-oxadiazolyl[1,2,4]), (5-{R₁₄ }-3-oxadiazolyl[1,2,4]) (5-{R₁₄}-2-oxadiazolyl[1,3,4]), (5-{R₁₄ }-2-thiadazolyl[1,3,4]), (4- or 5-{R₁₄}-2-thiazolyl), (4- or 5-{R₁₄ }-2-oxazolidinyl), (4- or 5-{R₁₄}-2-thiazolidinyl), (1-, 4- or 5-{R₁₄ }-2-imidazolidinyl). The remainingpreferred substituents for compounds of the Formula (II) are the same asthose listed above for compounds of the Formula (I), where applicable.

Exemplified preferred compound of Formula (II) are:

2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;

4-(3,4-bisdifluoromethoxyphenyl)-2-carbomethoxy-4-cyanocyclohexan-1-one;

2-carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one;

2-carbomethoxy-4-cyano-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;

2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one;

2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;

2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;

4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[2-(trimethylsilyl)ethoxycarbonyl)]-cyclohexan-1-one;

2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;

4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2,4-dicyanocyclohexan-1-one;and

2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one.

It will be recognized that some of the compounds of Formula (I) and (II)may exist in both racemic and optically active forms; some may alsoexist in distinct diastereomeric forms possessing distinct physical andbiological properties. All of these compounds are considered to bewithin the scope of the present invention.

Some compounds of Formula (I) or (II) may exist in a tautomeric form,such as the enol. This may be represented by the ═O being exocyclic tothe cyclohexane ring ##STR5## as contrasted to the endocyclic or--C(--OH)═C(R)-- moiety wherein the cyclohexane ring is now unsaturatedin the 1-2 position, i.e. cyclohex-1-ene, or ##STR6## and R is H inFormula (I) or Z" in Formula (II). It is also recognized that the2-position of the ring in the endocyclic form can be substituted (R)such as in the compounds of Formula (II).

The term "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" groups asused herein is meant to include both straight or branched chain radicalsof 1 to 10, unless the chain length is limited thereto, including, butnot limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like.

"Alkenyl" means both straight or branched chain radicals of 1 to 6carbon lengths, unless the chain length is limited thereto, includingbut not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl or3-methyl-2-propenyl.

The term "cycloalkyl" or "cyclalkyl alkyl" means groups of 3-7 carbonatoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, orcyclohexyl.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. Preferably the aryl is monocyclic, i.e., phenyl. The alkylchain is meant to include both straight or branched chain radicals of 1to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo.

"Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translation or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

The phase "TNF mediated disease or disease states" means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as "TNF"unless specifically delineated otherwise. Preferably TNF-60 isinhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of Formula (I) and (II) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) and (II) are useful in themethod of inhibiting or mediating the enzymatic or catalytic activity ofPDE IV and in treatment of disease states mediated thereby.

METHODS OF PREPARATION:

Preparing compounds of Formula (I) can be carried out by one of skill inthe art according to the procedures outlined in the Examples, infra. Thepreparation of any remaining compounds of Formula (I) not describedtherein may be prepared by the analogous processes disclosed hereinwhich comprises:

a) for compounds wherein X and X₁ are other than Br, I, NO₂, amine,formyl amine, or S(O)m' when m' is 1 or 2, reacting a compound ofFormula (2) ##STR7## wherein R₁ represents R₁ as defined in relation toFormula (I) or a group convertable to R₁ and X represents X as definedin relation to Formula (I) or a group convertable to X and X₃ representsX₃ as defined in relation to Formula (I) or a group convertable to X₃and X₁ is H, with a lithium halide and silyl halide in an appropriatesolvent followed by reduction with an appropriate reductant, such as asiloxane, to provide a compound of Formula (3) wherein X₄ is a halide.Alternatively, reduction of a compound of Formula (2) wherein X₁ is Hwith a suitable reductant, such as sodium borohydride, provides acompound of Formula (3) wherein X₄ is OH. Reaction of such a compound ofFormula (3) with, for example, phosphorous trichloride, thionylchloride, phosphorous tribromide, cupric bromide, or carbon tetrabromideand triphenylphosphine, also provides a compound of Formula (3) whereinX₄ is a halide; ##STR8## halide displacement by cyanide provides acompound of Formula (3) wherein X₄ is CN. Reaction of a compound ofFormula (3) wherein X₄ is CN with an excess of an acrylate, such asmethyl, ethyl, phenyl, benzyl or t-butyl acrylate, in the presence of abase, such as excess metal hydride or catalytic or excess quaternaryamine base, such as benzyltrimethylammonium hydroxide, in a suitablenon-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethanewhen a metal hydride base is used or these solvents or acetonitrile whena quaternary amine base is used, then provides a compound of Formula (4)in which X₄ is CN and R₁₆ is an alkyl, phenyl or benzyl group; ##STR9##reaction of a compound of Formula (4) with a base, such as excess metalhydride, in a suitable non-reacting solvent, such as tetrahydrofuran or1,2-dimethoxyethane, at an elevated temperature then provides a compoundof Formula (5) wherein X₄ is CN and R₁₆ is an alkyl, phenyl, or benzylgroup; l ##STR10## alternatively, a compound of Formula (5) [a subset ofthe compounds of Formula (II)] may be obtained directly from a compoundof Formula (3) wherein X₄ and R₁₆ are as described above by reactionwith an excess of an acrylate, such as methyl, ethyl, phenyl, benzyl, ort-butyl acrylate, with excess base, such as a metal hydride, in asuitable non-reacting solvent, such as tetrahydrofuran or1,2-dimethoxyethane, at an elevated temperature.

Treating a compound of Formula (5) with, e.g., sodium chloride inaqueous dimethylsulfoxide at elevated temperature, effectssaponification and decarboxylation of the ester moiety to provide acompound of Formula (I) in which R₃ is CN and Z is O. Alternatively, acompound of Formula (2) wherein X₁ is H may be homologated to a compoundof Formula (3) wherein X₄ is COOR₁₇ by any number of processes known inthe art, such as reaction with methyl methylsulfinyl-methyl sulfide anda base, such as sodium hydroxide, followed by treatment with, forexample, alcoholic (R₁₇ OH) acid. Reaction of such a compound of Formula(3) wherein X₄ is COOR₁₇ with an excess of an acrylate, such as methyl,ethyl, phenyl, benzyl, or t-butyl acrylate, and with excess base, suchas a metal hydride, in a suitable non-reacting solvent, such astetrahydrofuran or 1,2-dimethoxyethane, provides a compound of Formula(4) wherein X₄ is COOR₁₇ and R₁₆ and R₁₇ are independently an alkyl,phenyl, or benzyl group. Reaction of a compound of Formula (4) whereinX₄ is COOR₁₇ and R₁₆ and R₁₇ are independently an alkyl, phenyl, orbenzyl group with a base, such as excess metal hydride, in a suitablenon-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, atan elevated temperature then provides a compound of Formula (5) whereinX₁ is COOR₁₇ and R₁₆ and R₁₇ are independently an alkyl, phenyl orbenzyl group. Treatment of a such a compound of Formula (5) with, e.g.,sodium chloride in aqueous dimethylsulfoxide at elevated temperatureeffects saponification and decarboxylation of the β-keto ester moiety toprovide a compound of Formula (I) wherein R₃ is COOR₁₇ and Z is O,although under certain reaction conditions, some compounds of Formula(I) wherein R₃ is COOH and Z is O will also be obtained. The carboxylgroup of such a compound of Formula (I) may then be converted into anumber of esters, in which R₃ is COOR₈, or amides, in which R₃ is CONR₈R₈, using any of the very wide varieties of standard transformationsknown in the art. In some cases, the keto carbonyl of such a compound ofFormula (I) may require protection as, e.g., a ketal, prior to ester oramide formation, with liberation of the protected ketone underappropriate mild acidic conditions as the final step. The simple amidederivative, that in which R₃ is CONH₂ and Z is O, may be treated, afterappropriate protection of the ketone, with a dehydrating agent toprovide, after ketone deprotection, the compound of Formula (I) in whichR₃ is CN and Z is O.

Compounds of Formula (I) wherein R₃ is CHO and Z is O may be preparedfrom the compound of Formula (I) in which R₃ is CN and Z is O afterappropriate protection of the ketone as, e.g., a ketal, followed byreduction of the CN moiety with, e.g., diisobutylaluminum hydride,followed by appropriate workup and ketone deprotection.

Compounds of Formula (I) wherein R₃ is CH₂ OH and Z is O may be preparedby reduction of the compound of Formula (I) in which R₃ is CHO and ═Z isa ketal protecting group with, e.g., sodium borohydride, followed byappropriate workup and ketone deprotection.

Compounds of Formula (I) wherein R₃ is CH₂ NR₈ R₈ and Z is O may beprepared by reduction of the compound of Formula (I) in which R₃ is CNand ═Z is a ketal protecting group with, e.g., lithium aluminum hydrideor hydrogen in the presence of a catalyst, followed by appropriateworkup, standard alkylation by R₈ and then ketone deprotection.

Compounds of Formula (I) wherein R₃ is OH and Z is O may be preparedfrom the compound of Formula (I) in which R₃ is CHO and ═Z is a ketalprotecting group by, e.g., Bayer-Villiger oxidation of the aldehyde andester saponification to provide the compound of Formula (I) in which R₃is OH and ═Z is a ketal protecting group, followed by ketonedeprotection.

Compounds of Formula (I) wherein R₃ is halogen and Z is O may beprepared from the compound of Formula (I) in which R₃ is OH and ═Z is aketal protecting group by, e.g., dehydration to the olefin andhydrohalic acid addition to provide the compound of Formula (I) in whichR₃ is halogen and ═Z is a ketal protecting group, followed by ketonedeprotection.

Compounds of Formula (I) wherein R₃ is C.tbd.CR_(8') and Z is O may beprepared from the compound of Formula (I) in which R₃ is CHO and ═Z is aketal protecting group by reaction with a mixture of dimethyl(diazomethyl)phosphonate and potassium t-butoxide or other suitablebase, in an inert solvent,such as tetrahydrofuran, at reducedtemperature, followed by appropriate workup and ketone deprotection toprovide the compounds of Formula (I) wherein R₃ is C.tbd.CH;alternatively, prior to ketone deprotection, alkylation of the acetyleneunder the appropriate conditions with a strong base followed by analkylating agent, R₈ L, wherein L is a leaving group and R_(8') is notH, followed by ketone deprotection, provides compounds of Formula (I)wherein R₃ is C.tbd.CR₈ '.

Compounds of Formula (I) wherein R₃ is CH₂ F and Z is O may be preparedfrom the compound of Formula (I) wherein R₃ is CH₂ OH and ═Z is a ketalprotecting group by treatment with diethyl-aminosulfur trifluoride(DAST) followed by ketone deprotection.

Compounds of Formula (I) wherein R₃ is CHF₂ and Z is O may be preparedfrom the compound of Formula (I) wherein R₃ is CHO and ═Z is a ketalprotecting group by treatment with diethylaminosulfur trifluoride (DAST)followed by ketone deprotection.

Compounds of Formula (I) wherein R₃ is CF₃ and Z is O may be preparedfrom the compound of Formula (3) wherein X₂ is CF₃ using the proceduresdescribed above for preparation of the compounds of Formula (I) whereinR₃ is CN or COOR₁₆ and Z is O; the compound of Formula (3) wherein X₂ isCF₃ may be prepared in turn from the compound of Formula (2) wherein X₁is H either electrochemically by the method of Shono et al., J. Org.Chem., 56:2-4, 1991, or by treating a compound of Formula (6) ##STR11##wherein X₅ is, e.g., bromine, with a metallizing agent, such as an alkyllithium, in an inert solvent, such as tetrahydrofuran or1,2dimethoxyethane, at -78° C. followed by the trifluoroacetic acid ordifluoro acetic acid by the method of Nad et al., Izvest, 71, 1959;Chem. Abstr., 53, No. 14977 and 53, No. 17933, 1959, to provide acompound of Formula (2) wherein X₁ is CF₃, which is then thioketalizedwith, e.g., 1,3-propanedithiol and subsequently subjected todesulfurization with, e.g., Raney nickel.

The compounds of Formula (I) where R₃ is C₁ alkyl and Z is O may beprepared from the compound of Formula (I) wherein R₃ is CH₂ OH and ═Z isa protected ketone by reductive removal of the alcohol with lithium inammonia, with aluminum hydride, or by conversion of the alcohol to thecorresponding thiocarbamate followed by reduction with, e.g.,tributyltin hydride or trialkylsilyl hydride, and ketone deprotection;alternatively, the compounds of Formula (I) wherein R₃ is C₁ alkyl and Zis O may be prepared from the compound of Formula (I) wherein R₃ is CHOand ═Z is a protected ketone by thioketal formation, desulfurization andketal deprotection.

Compounds of Formula (I) where R₃ is C₂₋₄ alkyl or halogen substitutedC₂₋₄ alkyl and Z is O may be prepared by analogous deoxygenationprocedures from the corresponding alcohol derived from reaction of thecompound of Formula (I) wherein R₃ is CHO and ═Z is a protected ketonewith a metal alkyl or a halogen substituted C₂₋₄ metal alkyl reagent andsubsequent deprotection to liberate the ═Z ketone.

Compounds of Formula (I) wherein R₃ is vinyl and Z is O may be preparedby, e.g., Wittig or other olefination reaction of the compound ofFormula (I) wherein R₃ is CHO and ═Z is a protected ketone,andsubsequent deprotection to liberate the ═Z ketone.

Compounds of Formula (I) wherein R₃ is cyclopropyl and Z is O may beprepared from the compound of Formula (I) wherein R₃ is vinyl and ═Z isa protected ketone by reaction with, e.g., methylene iodide andzinc-copper couple, with subsequent deprotection to liberate to ═Zketone.

Alternatively, certain compounds of Formula (I) wherein Z is O and R₃ isCOOR₈ (or COOR₁₆) may be prepared by reducing the double bond of thecyclohexenone synthetic intermediates produced by the method ofParkinson and Pinhey, J. Chem. Soc. Perkin Trans. I, 1053-7, 1991,incorporated herein by reference in its entirety. Similar double bondreduction of the corresponding synthetic intermediates wherein R₃ is CNderived by analogous procedures using 4-cyano-3-cyclohexan-1-one and/or4-cyano-2-cyclohexen-1-one may provide certain compounds of Formula (I)wherein Z is O and R₃ is CN.

Most compounds of Formula (I) wherein Z is not O are prepared from thecorresponding compounds of Formula (I) wherein Z is O by reaction withthe appropriate amine, alcohol, or thiol, in the presence of a catalystor with removal of water, if required, as described in the proceduresoutlined in the Examples, infra; however, when R₃ is CHO, this R₃ groupmay require protection as, e.g., a ketal, during reaction followed bydeprotection.

b) Compounds of Formula (I) wherein X or X₃ is formyl amine and Z is Omay be prepared by formulating, at the last step, a compound wherein ═Zis a protected ketone and X is NH₂, obtained by removal of a protectinggroup from the amine functionality; such protective groups are wellknown to those skilled in the art, See Greene, T. and Wuts, P. G. M.,Protecting Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons,New York (1991).

c) Compounds of Formula (I) wherein X or X₃ is Br or I and Z is O may beprepared from a similarly deprotected amine by diazotization of theamine and diazonium displacement via Sandmeyer reaction.

d) Compounds of Formula (I) wherein X or X₃ is NO₂ and Z is O may beprepared from a similarly deprotected amine by oxidation of the amine tothe nitro group.

e) Compounds of Formula (I) wherein Y is S(O)m' when m' is 1 or 2 and Zis O may be prepared from the compounds of Formula (I) wherein Y is S byoxidation of the SR₂ moiety under conditions well known to those skilledin the art.

Compounds of Formula (II) wherein R₁₄ in C(O)OR₁₄ of the Z" group isother than an alkyl, phenyl, or benzyl group are obtained from compoundsof Formula (5) or from other compounds of Formula (II) by standardtransesterification procedures. Similarly, other compounds of theFormula (II), e.g., Z" amides, aldehydes, ketones, hydrazides, etc., maybe prepared from other compounds of the Formula (II) by, e.g., standardfunctional group manipulation of the Z" group, either preceeding orfollowing functional group manipulation of the R₃ group. In some cases,appropriate protection of certain chemically sensitive R₃ groups and/orthe keto (═O) moiety of the Formula (II) compound may be required duringfunctional group manipulation of the Z" group, with subsequentdeprotection providing the desired Formula (II) compound. Some suchmanipulations of the Z" group may be accomplished by the processesdescribed in co-pending U.S. application Ser. No. 862,030 filed 2 Apr.1992 and its corresponding continuation-in-part application U.S. Ser.No. 968,762 filed 30 Oct. 1992. In other cases, some compounds ofFormula (II) may be converted to other compounds of Formula (II) bymanipulation of the R₃ group using the general technique described aboveand, when necessary, using appropriate protection and deprotection ofchemically sensitive functionalities, such as the keto (═O) moiety orchemically sensitive moieties of the Z" group. Also, some compounds ofFormula (II) may be prepared by reaction of an appropriate compound ofFormula (I) with an appropriate base in the appropriate proportionsunder the appropriate conditions followed by reaction with ahaloformate, such as methyl or ethyl chloroformate, or by treatment ofan appropriate compound of Formula (I) with methyl methoxy magnesiumcarbonate;such compounds of the Formula (II) may then be converted toother compounds of the Formula (II) by the techniques described aboveand below.

In addition, some compounds of the formula (II) may be prepared byreacting a compound of the Formula (3) wherein R₁ represents R₁ asdefined in relation to Formula (I) or a group convertable to R₁ and X,X₂ and X₃ represent X, X₂ and X₃ as defined in relation to Formula (I)or a group convertable to X, X₂ or X₃ and R₃ represents R₃ as defined inrelation to Formula (I) or a group convertable to R₃, and X₄ is CN withan excess of acrylonitrile in the presence of a base, such as excessmetal hydride, or catalytic or excess quaternary amine base, such asbenzyltrimethylammonium hydroxide, in a suitable non-reacting solvent,such as tetrahydrofuran or 1,2-dimethoxyethane when a metal hydride baseis used or these solvents or acetonitrile when a quaternary amine baseis used, to provide a compound of the Formula (7) ##STR12## wherein X₄is CN; reaction of a compound of the Formula (7) with a base, such asexcess metal hydride, in a suitable non-reacting solvent, such astetrahydrofuran or 1,2-dimethoxyethane, at an elevated temperature thenprovides a compound of the Formula (8) ##STR13## wherein X₄ is CN and X₅and X₆ are both H; alternatively, a compound of the Formula (8) may beobtained directly from a compound of Formula (7) wherein X₄ is asdescribed above by reaction with an excess of optionally R₂ -substitutedacrylonitrile, with excess base, such as a metal hydride, in a suitablenon-reacting solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, atan elevated temperature.

Treatment of a compound of the Formula (8) with an acid, e.g., 6Nhydrochloric acid at ambient or elevated temperature, in a solvent, suchas ethanol, with or without a co-solvent, such as chloroform, provides acompound of Formula (9). ##STR14##

Compounds of the Formula (10) ##STR15## wherein X₅ is H, are prepared byheating compounds of the Formula (9) in a solution of hydrazoic acidgenerated in situ by, e.g., admixture of an alkalai metal azide, such assodium azide, with an ammonium halide, such as triethylaminehydrochloride, in a polar non-protic solvent such asN-methylpyrrolidinone.

Using the series of reactions outlined above begining with reaction ofan appropriate compound of Formula (3) but with a 2-(R₂)- or 3-(R₂-acrylate provides, respectively and sequentially, the 2,6-(R₂)₂ - or3,5-(R₂)₂ -pimelates of Formula (4), the 2,6-(R₂)₂ - or 3,5-(R₂)₂-2-(COOR₁₆)-cyclohexanones of Formula (5) and then the 2,6-(R₂)₂ - or3,5-(R₂)₂ -cyclohexanones of Formula (I). Similarly, starting withreaction of an appropriate compound of Formula (3) but with a2,3-(R₂)₂ - or 3,3-R₂)₂ -acrylate provides, respectively andsequentially, the 2,3,5,6-(R₂)₄ - or 3,3,5,5-(R₂)₄ -pimelates of Formula(4),the 2,3,5,6-(R₂)₄ - or 3,3,5,5-(R₂)₄ -2-(COOR₁₆)-cyclohexanones ofFormula (5) and then the 2,3,5,6-(R₂)₄ - or 3,3,5,5-(R₂)₄-cyclohexanones of Formula (I). Likewise, starting with reaction of anappropriate compound of Formula (3) but with a mixture of appropriateacrylates, e.g., methyl acrylate and methyl 3-(R₂)- or 2,3-(R₂)₂-acrylate, provides, respectively and sequentially, e.g., 3-(R₂)- or2,3-(R₂)₂ -pimelates of Formula (4), the 3-(R₂)-, 5-(R₂)-, 5,6-(R₂)₂ -,or 2,3-(R₂)₂ -2-COOR₁₆)-cyclohexanones of Formula (5) and then the3-(R₂)- or 2,3-(R₂)₂ -(R₂)₄ -cyclohexanones of Formula (I).Alternatively, reaction of an appropriate compound of Formula (I) withan appropriate base in the appropriate proportions under the appropriateconditions followed by reaction with an alkylating agent, R₂ L, whereinL is a leaving group, provides the 2-(R₂)-, 2,2-(R₂)₂ -, 2,6-(R₂)₂ -, or2,2,6,6-(R₂)₄ -cyclohexanones of Formula (I); similar reaction of anappropriately alkylated compound of Formula (I), e.g., 3,5-(R₂)₂ - or2,6-(R₂)₂ -cyclohexanone, provides, e.g., 2,3,5-(R₂)₃ - or 2,2,6-(R₂)₃-cyclohexanone of Formula (I), respectively. Likewise, similar reactionof a compound of Formula (5) provides, e.g., 2-(R₂)-, 2,6-(R₂)₂ -, or2,6,6-(R₂)₃ -2-(COOR₁₆)-cyclohexanones of Formula (5); such compounds ofFormula (5) may then be converted to the corresponding compounds ofFormula (I) by ester saponification and decarboxylation as describedabove. Such compounds of Formula (I) may then be converted to othercompounds of Formula (I) using the general techniques and, whennecessary, appropriate protection and deprotection of chemicallysensitive functionalities, described above; likewise, such compounds ofFormula (II) may be converted to other compounds of Formula (II) usingthe general techniques and, when necessary, appropriate protection anddeprotection of chemically sensitive functionalities, described above.

The following examples are set out to illustrate how to make thecompounds of this invention and methods for determining associatedtherapeutic activity. These examples are not intended to limit theinvention in any manner, their purpose is illustrative rather thanlimiting.

EXAMPLE 12-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cyclohexan-1-one1a. (3-Cyclopentyloxy-4-methoxyphenyl)acetonitrile

To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173mmol) followed by the dropwise addition of trimethylsilylchloride (17.4mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C.,1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise andthe resulting mixture was allowed to warm to room temperature. Afterstirring for 3h, the mixture was separated into two layers. The lowerlayer was removed, diluted with methylene chloride and filtered throughCelite. The filtrate was concentrated under reduced pressure, dissolvedin methylene chloride and refiltered. The solvent was removed in vacuoto provide a light tan oil. To a solution of this crudea-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylflormamide (160 mL)under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol)and the resulting mixture was stirred at room temperature for 18 h, thenpoured into cold water (600 mL) and extracted three times with ether.The organic extract was washed three times with water, once with brineand was dried (potassium carbonate). The solvent was removed in vacuoand the residue was purified by flash chromatography, eluting with 10%ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p.32°-34° C.; an additional quantity (1.3 g) of slightly impure materialalso was isolated.

1b. Dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate

To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g,30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was addeda 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and themixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) wasadded carefully, the reaction mixture was maintained at reflux for 5 andthen cooled. The mixture was diluted with ether, was washed once with 1Nhydrochloric acid and once with brine, was dried (magnesium sulfate) andthe solvent was removed in vacuo. The solid residue was triturated with5% ethanol/hexane to provide a white solid (9 g, 74%): m.p. 81°-82° C.;and additional 1.1 g (9%) was also obtained from the filtrate.

Analysis Calc. for C₂₂ H₂₉ NO₆ : C 65.49, H 7.25, N 3.47; found: C65.47, H 7.11, N 3.49.

1c.2-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a solution of dimethyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol)in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was addedsodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). Themixture was heated to reflux for 4.5 h, then was cooled to roomtemperature and was stirred for 16 h. Water was added and the reactionmixture was partitioned between ether and acidic water. The organicextract was dried (magnesium sulfate) and the solvent was removed invacuo. The residue was purified by flash chromatography, eluting with3:1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%).

Analysis Calc. for C₁₉ H₂₃ NO₃.1/4H₂ O: C 67.09, H 6.84, N 3.72; found C66.92, H 6.61, N 3.74.

EXAMPLE 24-(3,4-Bisdifluoromethoxyphenyl)-2-carbomethoxy-4-cyanocyclohexan-1-one2a. 3,4-Bisdifluoromethoxybenzaldehyde

A vigorously stirred mixture of 3,4-dihydroxybenzaldehyde (40 g, 290mmol) and powdered potassium carbonate (120 g, 870 mol) indimethylformamide (500 mL) was heated under an atmosphere ofchlorodifluoromethane at 80° C. for 7 h and then was stirred at roomtemperature overnight. The mixture was diluted with ether and wasfiltered. The filtrate was concentrated under reduced pressure, theresidue was partitioned between ether and aqueous potassium carbonateand was extracted five times with ether. The organic extract was washedwith aqueous potassium carbonate and dried (potassium carbonate). Thesolvent was removed in vacuo and the residue was purified by flashchromatography, eluting with 4;1 hexanes/ether, to provide an oil (26.2g, 38%).

2b. 3,4-Bisdifluoromethoxybenzyl alcohol

3,4-Bisdifluoromethoxybenzaldehyde (26.2 g, 110 mmol) in absoluteethanol (150 mL) was treated with sodium borohydride (8.32 g, 220 mmol)under an argon atmosphere at room temperature for 0.5 h. Ten percentaqueous sodium hydroxide (130 mL) was added, the ethanol was removed invacuo, the mixture was partitioned between ether and water and wasextracted twice with ether. The organic extract was dried (magnesiumsulfate) and evaporated to a pale yellow oil (26.4 g, 100%).

2c. 2-(3,4-Bisdifluoromethoxyphenyl)acetonitrile

A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol)and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argonatmosphere was treated with thionyl chloride (9.62 mL, 130 mmol) and themixture was heated at reflux for 1 h. The solvent was removed, ether wasadded and the precipitate was removed by filtration. The filtrate wasconcentrated to a purple oil. To a solution of this3,4-Bisdifluoromethoxybenzyl chloride in dimethylflormamide (200 mL)under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol).The resulting mixture was stirred and gently heated at 45° C. for 3 h,was cooled and was concentrated. The mixture was partitioned betweenether and 5% aqueous sodium carbonate and was extracted five times withether. The organic extract was washed once with brine, was dried (sodiumcarbonate) and the solvent was removed in vacuo to provide an oil (27g).

2d. Dimethyl 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)-4-cyanopimelate

To a solution of 2-(3,4-bisdifluoromethoxyphenyl)acetonitrile (27 g, 108mmol) and a 40% solution of Triton-B in methanol (5 mL, 11 mmol) inacetonitrile (450 mL) under an argon atmosphere at room temperature wasadded methyl acrylate (48.6 mL, 540 mmol). After 20 min, aqueoushydrochloric acid (3N, 20 mL) was added and the mixture wasconcentrated. The residue was partitioned between water and ether, wasextracted twice with ether, the ether layer was dried (magnesiumsulfate) and evaporated in vacuo to provide a yellow oil (45.32 g, 99%).

2e.4-(3,4-Bisdifuloromethoxyphenyl)-2-carbomethoxy-4-cyanocyclohexan-1-one

To a solution of dimethyl4-(3,4-bisdifluoromethoxyphenyl)-4-cyanopimelate (45.32 g, 107 mmol) indry 1,2-dimethoxyethane (450 mL) under an argon atmosphere was addedsodium hydride (80% dispersion in mineral oil, 13 g, 432 mmol). Theresulting mixture was refluxed for 1 h, was cooled to room temperature,was quenched with water and was concentrated. The mixture waspartitioned between ether and acidic brine, was extracted twice withether, the organic layer was dried (magnesium sulfate) and the solventwas removed in vacuo. The residue was purified by flash chromatography,eluting with 3:1 hexanes/ethyl acetate, to provide a pale-orange oil(19.5 g, 46.6%).

Analysis Calc. for C₁₇ H₁₅ F₄ NO₅ : C 52,45, H 3.88, N 3.60; found: C52.60, H 4.07, N 3.22.

EXAMPLE 32-Carbomethoxy-4-cyano-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one3a. 3-Difluoromethoxy-4-methoxybenzaldehyde

A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (2.5 g,16.4 mmol) and powdered cesium carbonate (5.6 g, 17.2 mmol) indimethylformamide (50 mL) was heated under an atmosphere ofchlorodifluoromethane at 80° C. for 4 h. The mixture was allowed tocool, was poured into water and was extracted three times with ethylacetate. The organic extract was dried (sodium sulfate) and the solventwas removed in vacuo. Purification by flash chromatography, eluting with5% ethyl acetate/chloroform, provided an oil (2 g, 60%).

3b. (3-Difluoromethoxy-4-methoxyphenyl)acetonitrile

To 3-difluoromethoxy-4-methoxybenzaldehyde (2 g, 9.8 mmol) was addedlithium bromide (1.7 g, 19.6 mmol) and acetonitrile (11 mL). Upondissolution, the reaction mixture was cooled to 0° C.Trimethylsilylchloride (1.86 mL, 14.7 mmol) was slowly added and thereaction mixture was allowed to warm to room temperature and was stirredfor 15 min. The reaction mixture was again cooled to 0° C.,1,1,3,3-tetramethyldisiloxane (2.6 mL, 14.7 mmol) was added and theresulting mixture was allowed to warm to room temperature. Afterstirring for 3 h, the mixture was separated into two layers. The lowerlayer was removed, diluted with methylene chloride and filtered. Thefiltrate was concentrated under reduced pressure, dissolved in methylenechloride and refiltered. The solvent was removed in vacuo to provide anoil, which was dissolved in dimethylflormamide (10 mL) under an argonatmosphere and treated with sodium cyanide (1.08 g, 22 mmol). Theresulting mixture was stirred at room temperature overnight, then pouredinto cold water (250 mL) and extracted three times with ethyl acetate.The organic extract was washed three times with water, once with brineand was dried (potassium carbonate). The solvent was removed in vacuo toprovide a yellow oil (1.54 g, 74%), which was used without purification.

3c. Dimethyl 4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)pimelate

To a solution of (3-difluoromethoxy-4-methoxyphenyl)acetonitrile (1.54g, 7.2 mmol) in acetonitrile (78 mL) under an argon atmosphere was addeda 40% solution of Triton-B in methanol (0.33 mL, 0.72 mmol). Theresulting mixture was heated to reflux and methyl acrylate (13 mL, 144mmol) was added cautiously. After 3 h, the reaction was cooled to roomtemperature, water was added and the mixture was concentrated. Theresidue was partitioned between aqueous hydrochloric acid and ethylacetate, was extracted twice with ethyl acetate, the organic layer wasdried (magnesium sulfate) and evaporated. Purification by flashchromatography, eluting with 2:1 hexanes/ethyl acetate, provided a foam(1.7 g, 61%).

3d.2-Carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexane-1-one

To a suspension of sodium hydride (95%, 0.33 g, 13.2 mmol) in dry1,2-dimethoxyethane (70 mL) under an argon atmosphere was added asolution of dimethyl4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)pimelate (1.7 g. 4.4 mmol)in dry 1,2-dimethoxyethane (70 mL). The resulting mixture was refluxedfor 5h, cooled to room temperature, stirred overnight and quenched withwater. The mixture was partitioned between ethyl acetate and acidicwater, extracted three times with ethyl acetate, the organic layer wasdried (magnesium sulfate) and the solvent was removed in vacuo.Purification by flash chromatography, eluting with 3:1 hexanes/ethylacetate, provided an oil (0.51 g, 33%, 51% based on recovered startingmaterial).

EXAMPLE 42-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one4a. 3-Cyclopropylmethoxy-4-methoxybenzaldehyde

A vigorously stirred mixture of 3-hydroxy-4-methoxybenzaldehyde (20 g,131 mmol), chloromethylcyclopropane (18.2 mL, 197 mmol) and powderedpotassium carbonate (27.3 g, 197 mol) in dimethylflormamide (400 mL) washeated under an argon atmosphere at 80° C. for 9 h. The mixture wasallowed to cool and was filtered through Celite. The filtrate wasconcentrated under reduced pressure, the residue was extracted twicewith ethyl acetate, the organic extract was washed five times withsaturated aqueous sodium carbonate and was dried (sodium sulfate). Thesolvent was removed in vacuo to provide an off-white solid (21.2 g,78%): m.p. 67°-69° C.

4b. (3-Cyclopropylmethoxy-4-methoxyphenyl)acetonitrile

To 3-cyclopropylmethoxy-4-methoxybenzaldehyde (21.2 g, 103 mmol) wasadded lithium bromide (17.8 g, 206 mmol) and acetonitrile (110 mL). Upondissolution, the reaction mixture was cooled to 0° C.Trimethylsilylchloride (19.6 mL, 154 mmol) was slowly added and thereaction mixture was allowed to warm to room temperature and was stirredfor 15 min. The reaction mixture was again cooled to 0° C.,1,1,3,3-tetramethyldisiloxane (27.2 mL, 154 mmol) was added and theresulting mixture was allowed to warm to room temperature. Afterstirring for 2 h, the mixture was separated into two layers. The lowerlayer was removed, was diluted with methylene chloride,was filtered andthe filtrate was concentrated under reduced pressure; this procedure wasrepeated a total of three times. The resulting light tan oil wasdissolved in dimethylflormamide (90 mL) under an argon atmosphere andwas treated with sodium cyanide (11.3 g, 232 mmol). The resultingmixture was stirred at room temperature for 2 h, then poured into coldwater and extracted twice with ethyl acetate. The combined organicextract was washed three times with water, once with brine and was dried(sodium sulfate). The solvent was removed in vacuo to provide an oil(21.4 g, 96%), which was used without purification.

4c. Dimethyl-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)pimelate

To a solution of (3-cyclopropylmethoxy-4-methoxyphenyl)acetonitrile(21.4 g, 98.6 mmol) in acetonitrile (400 mL) under an argon atmospherewas added a 40% sodium of Triton-B in methanol (4.5 mL, 9.9 mmol). Theresulting mixture was heated to reflux and methyl acrylate (178 mL, 197mmol) was added cautiously. After 3 h, the reaction was cooled to roomtemperature and concentrated. The residue was partitioned between 10%aqueous hydrochloric acid and ethyl acetate, was extracted three timeswith ethyl acetate,the organic layer was dried (potassium carbonate) andevaporated. Purification by flash chromatography, eluting with 2:1hexanes/ethyl acetate, provided an oil (27 g, 71%).

4d.2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-one

To a solution of dimethyl4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)pimelate (10.4 g, 26.7mmol) in dry 1,2-dimethoxyethane (500 mL) under an argon atmosphere wasadded sodium hydride (80% dispersion in mineral oil, 2.5 g, 31.2 mmol).The resulting mixture was refluxed for 4 h, cooled to room temperatureand quenched with water. The mixture was partitioned between ethylacetate and acidic water, extracted three times, the organic layer wasdried (magnesium sulfate) and the solvent was removed in vacuo. Theproduct was purified by flash chromatography, eluting with 2:1hexanes/ethyl acetate, to provide an oil (9 g, 95%).

Analysis Calc. for C₂₀ H₂₃ NO₅.1/8H₂ O: C 66.79, H 6.52, N 3.89; found C66.62, H 6.43, N 3.92.

EXAMPLE 52-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one5a. 4-Difluoromethoxy-3-hydroxybenzaldehyde

A vigorously stirred mixture of 3,4-dihydroxybenzaldehyde 50 g, 362mmol) and powdered potassium carbonate (50 g, 362 mol) indimethylflormamide (250 mL) was heated at 100° C. under an atmosphere ofchlorodifluoromethane using a -78° C. condenser for 5.5 h. An additionalquantity of potassium carbonate (10 g) was added and the reaction wascontinued for another 0.5 h. The mixture was allowed to cool, wasacidified to pH 5-6 with concentrated hydrochloric acid and wasconcentrated under reduced pressure. The residue was partitioned betweenether and 3N aqueous hydrochloride and was extracted five times withether. The organic extract was dried (magnesium sulfate) and the solventwas removed in vacuo. The residue was purified by flash chromatography,eluting with 2:1 hexanes/ethyl acetate, providing a yellow solid, whichwas triturated with ethyl acetate/hexanes to provide, in three crops, awhite solid (12.1 g. 18%): m.p. 84°-82° C.

5b. 3-Cyclopentyloxy-4-difluoromethoxybenzaldehyde

To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde 2.9 g, 15 mmol)and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide(15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL,23 mmol) and the mixture was stirred and heated at 50° C. for 1 h and at80°-85° C. 1.5 h. The mixture was allowed to cool and was partitionedbetween ethyl acetate and water. The organic extract was washed threetimes with water, was dried (sodium sulfate) and the solvent was removedin vacuo. Purification by flash chromatography, eluting with 20-30%ether/hexanes, provided a yellow solid (3.5 g, 89%).

5c. (3-Cyclopentyloxy-4-difluoromethoxyphenyl)acetonitrile

To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl)benzaldehyde(3.4 g, 13.4 mmol) in absolute ethanol (33 mL) under an argon atmosphereat room temperature and was added sodium borohydride (1.06 g, 28 mmol).After 20 min, 10% aqueous sodium hydroxide (15 mL) was added, theethanol was removed in vacuo and the aqueous residue was extracted threetimes with ether. The organic extract was washed twice with brine, wasdried (magnesium sulfate) and evaporated to a pale yellow oil (3.44 g).A solution of this alcohol (1.52 g, 5.89 mmol) and pyridine (0.48 mL, 6mmol) in alumina-dried chloroform (15 mL) under an argon atmosphere wastreated with thionyl chloride (0.52 mL, 7.08 mmol) and the mixture washeated at reflux for 1 h. The solvent was removed, ether was added andthe precipitate was removed by filtration. The filtrate was concentratedto a pale yellow oil, which was dissolved in dimethylformamide (10 mL)under an argon atmosphere and treated with sodium cyanide (0.58 g, 11.8mmol). After stirring at room temperature for 72 h, the mixture waspartitioned between 5% aqueous sodium carbonate and ether. The organicextract was washed four times with water, was dried (potassiumcarbonate) and evaporated. Purification by flash chromatography, elutingwith 15-20% ethyl acetate/hexanes, provided a pale yellow solid (3.2 g,90%): m.p. 39°-41° C.

5d. Dimethyl4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)pimelate

To a solution of (3-cyclopentyloxy-4-difluoromethoxyphenyl)acetonitrile(1.8 g, 6.7 mmol) in acetonitrile (35 mL) under an argon atmosphere wasadded a 40% solution of Triton-B in methanol (0.31 mL, 0.67 mmol). Theresulting mixture was heated to reflux and methyl acrylate (6.1 mL, 67.2mmol) was added cautiously. After another 20 min, the reaction wascooled to room temperature and concentrated. The residue was partitionedbetween aqueous hydrochloric acid and ether, the organic layer was dried(magnesium sulfate) and evaporated to an oil (3.1 g, 100%).

5e.2-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexane-1-one

To a solution of dimethyl4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)pimelate (3.1 g, 6.7mmol) in dry 1,2-dimethoxyethane (50 mL) under an argon atmosphere wasadded sodium hydride (80% dispersion in mineral oil, 0.81 g, 27 mmol).The resulting mixture was refluxed for 20 min, additional1,2-dimethoxyethane (50 mL) was added and the mixture was refluxed foranother 70 min. The mixture was cooled to 0° C., was acidified withdilute hydrochloric acid and was concentrated. The mixture waspartitioned between ether and dilute hydrochloric acid the organic layerwas dried (magnesium sulfate) and the solvent was removed in vacuo. Theproduct was purified by flash chromatography, eluting with 85:15hexanes/ethyl acetate, to provide a white solid (0.76 g, 37%): m.p.109°-110.5° C.

Analysis Calc. for C₂₁ H₂₃ F₂ NO₅ : C 61.91, H 5.69, N 3.44; found: C61.83, H 5.66, N 3.39.

EXAMPLE 62-Carbomethoxy-4-cyano-4-(3=cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one6a. 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehyde

To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (19.55 g, 104mmol) and potassium carbonate (21.56 g, 156 mmol) in dimethylformamide(150 mL) under an argon atmosphere at 60° C. was addedbromomethylcyclopropane (15.13 mL, 156 mmol) and the mixture was stirredand heated at 65° C. After 1.5 h, the mixture was allowed to cool andwas filtered. The filtrate was concentrated under reduced pressure andthe residue was partitioned between ethylacetate and water and wasextracted four times with ethyl acetate. The organic extract was washedtwice with water and was dried (sodium sulfate). The solvent was removedin vacuo to provide an oil (26.4 g).

6b. 3-Cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol

Crude 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (26.4 g) inabsolute ethanol (200 mL) was treated with sodium borohydride (8.23 g,217 mmol) under an argon atmosphere at room temperature for 0.33 h. Tenpercent aqueous sodium hydroxide (150 mL) was added, the ethanol wasremoved in vacuo and the aqueous residue was extracted three times withether. The organic extract was washed twice with brine, was dried(sodium sulfate), was filtered and was evaporated to a pale yellow oil(24.4 g).

6c. 3-Cyclopropylmethoxy-4-difluoromethoxybenzyl chloride

A solution of crude 3-cyclopropylmethoxy-4-difluoromethoxybenzyl alcohol(24.4 g) and pyridine (9.8 mL, 120 mmol) in chloroform (150 mL) under anargon atmosphere was treated with thionyl chloride (8.0 mL, 110 mmol)and the mixture was heated at reflux for 1 h. The solvent was removed,ether was added and the precipitate was removed by filtration. Thefiltrate was concentrated to a pale yellow oil (26 g).

6d. (3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)acetonitrile

To 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride (26 g) indimethylflormamide (150 mL) under an argon atmosphere was added sodiumcyanide (9.7 g, 198 mmol). The resulting mixture was stirred at roomtemperature and heated gently for 2 h, then cooled and concentrated. Themixture was partitioned between basic brine and ether and extractedtwice. The organic extract was washed with brine and was dried (sodiumsulfate). The solvent was removed in vacuo to provide an orange-brownoil (24 g), which was used without purification.

6e. Dimethyl4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate

To a solution of crude(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)acetonitrile (24 g) inacetonitrile (500 mL) under an argon atmosphere was added a 40% solutionof Triton-B in methanol (4.3 mL, 9.5 mmol). The resulting mixture washeated to reflux and methyl acrylate (43 mL, 470 mmol) was addedcautiously. After 20 min. The reaction was cooled to room temperatureand water and dilute hydrochloric acid were added and the mixture wasconcentrated. The residue was partitioned between water and ether, theorganic layer was dried (magnesium sulfate) and evaporated to anorange-brown oil (41 g).

6f.2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one

To a suspension of sodium hydride (80% dispersion in mineral oil, 11.6g, 388 mmol) in dry 1,2-dimethoxyethane (700 mL) under an argonatmosphere was added a solution of crude dimethyl4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pimelate (41 g)in dry 1,2-dimethoxyethane (700 mL). The resulting mixture was heated at60° C. for 1 h, cooled to room temperature, quenched with dilute aqueoushydrochloric acid and concentrated. The residue was diluted with water,was acidified to pH 3 and was extracted twice with methylene chloride.The organic extract was washed with acidic water, was dried (sodiumsulfate) and the solvent was removed in vacuo. Purification by flashchromatography, eluting with methylene chloride, followed by triturationwith cold ether provided a solid (17.7 g, 43% from3-cyclopropylmethoxy-4difluoromethoxybenzaldehyde): m.p. 115°-116° C.

Analysis Calc. for C₂₀ H₂₁ F₂ NO₅ : C 61.06, H 5.38, N 3.56; found: C61.16, H 5.40, N 3.52.

EXAMPLE 7 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one(0.80 g, 2.15 mmol), dimethyl sulfoxide (16 mL), water (1 mL) and sodiumchloride (0.8 g) under an argon atmosphere was heated at 140°-145° C.for 5 h. The reaction mixture was cooled and concentrated. The residuewas purified by flash chromatography, eluting with 3:1 hexanes/ethylacetate, to provide a yellow solid. Trituration with hexanes/ethylacetate yielded a white solid (0.52 g, 77%): m.p. 111°-112° C.

Analysis Calc. for C₁₉ H₂₃ NO₃ : C 72.82, H 7.40, N 4.47; found: C72.72, H 7.39, N 4.48.

EXAMPLE 8 4(3,4-Bisdifuloromethoxyphenyl)-4-cyanocyclohexan-1-one

A mixture of2-carbomethoxy-4-(3,4-bisdifuloromethoxyphenyl)-4-cyanocyclohexan-1-one(0.55 g, 1.4 mmole), dimethyl sulfoxide (8 mL), water (0.5 mL) andsodium chloride (0.5 g) under an argon atmosphere was heated at140°-145° C. for 4 h.

The reaction mixture was cooled to room temperature and concentrated.The residue was partitioned between ether and water, the organic layerwas dried (magnesium sulfate) and the solvent was removed in vacuo. Theproduct was purified by flash chromatography, eluting with 1:1hexanes/ether. The residue was partitioned between water and ethylacetate and the organic layer was evaporated to yield a yellow solid.Trituration from the mineral amount of ethyl acetate/hexanes provided asolid (0.3 g, 63.6%): m.p. 64°-66° C.

Analysis Calc. for C₁₅ H₁₃ NO₃ F₄ : C 54.39, H 3.96, N 4.23; found: C54.25, H 3.96, N 4.20.

EXAMPLE 9 4-Cyano-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one(0.51 g, 1.44 mmole), dimethyl sulfoxide (11 mL), water (1 mL) andsodium chloride (0.53 g) under an argon atmosphere was heated at 150° C.for 5 h. The reaction mixture was partitioned between ethyl acetate andwater and extracted three times with ethyl acetate. The combined organicextract was washed twice with water, once with brine, was dried(potassium carbonate) and the solvent was removed in vacuo. The productwas purified by flash chromatography, eluting with 2:1 hexanes/ethylacetate, to provide an oil (0.36 g, 85%).

Analysis Calc. for C₁₅ H₁₅ NO₃ F₂.1/8H₂ O: C 60.55, H 5.17, N 4.71;found: C 60.42, H 5.07, N 4.77.

EXAMPLE 104-Cyano-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one(1.7 g, 4.7 mmole), dimethylsulfoxide (34 mL), water (3 mL) and sodiumchloride (1.6 g) under an argon atmosphere was heated at 150° C. for 4h, was stirred at room temperature overnight and was concentrated. Theresidue was partition between ethyl acetate and water and extractedthree times with ethyl acetate. The combined organic extract was washedtwice with water, once with brine, was dried (magnesium sulfate) and thesolvent was removed in vacuo. The product was purified by flashchromatography, eluting with 2:1 hexanes/ethyl acetate, to provide asolid (1.09 g, 77%): m.p. 116°-118° C.

Analysis Calc. for C₁₈ H₂₁ NO₃.1/8H₂ O: C 71.68, H 7.10, N, 4.64; found:C 71.51, H 7.03, N 4.55.

EXAMPLE 114-Cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one(0.98 g, 2.4 mmole), dimethyl sulfoxide (10 mL), water (0.62 mL) andsodium chloride (0.62 g) under an argon atmosphere was heated at 145° C.for 5 h. The reaction mixture was cooled to room temperature andconcentrated. The residue was partitioned between ether and water, theorganic layer washed with water, was dried (magnesium sulfate) and thesolvent was removed in vacuo. The product was purified by flashchromatography, eluting with 20-30% ethyl acetate/hexanes. The isolatedresidue was dissolved in ethyl acetate,this was washed twice with dilutesodium hydroxide, once with water, once with brine and then was driedand evaporated to yield a solid (0.2 g, 23.6%): m.p. 76°-78° l C.

Analysis Calc. for C₁₉ H₂₁ F₂ NO₃.1/6H₂ O: C 64.76, H 6.10, N 3.97;found; C 64.76, H 6.04, N 3.89.

EXAMPLE 124-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one(0.5 g, 1.27 mmol), dimethyl sulfoxide (10 mL), water (1 mL) and sodiumchloride (0.5 g) under an argon atmosphere was heated at 145°-150° C.for 4.5 h. The reaction mixture was cooled to room temperature andconcentrated. The residue was partitioned between ethyl acetate andwater, extracted twice with ethyl acetate,the organic layer was washedtwice with water and once with brine, was dried (sodium sulfate) and thesolvent was removed in vacuo. The product was purified by flashchromatography, eluting with 20-25% ethyl acetate/hexanes,and theresultant solid was triturated with ether/hexane and then with coldether to provide a solid (0.22 g, 51.6%): m.p. 85.5-86.5° C.

Analysis Calc. for C₁₈ H₁₉ F₂ NO₃ : C 64.47, H 5.71, N 4.18; found: C64.28, H 5.63, N 4.20.

EXAMPLE 13 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-oneoxime

To a solution of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.125 g,0.4 mmol) in pyridine (2 mL) was added hydroxyl amine hydrochloride(0.031 g, 0.44 mmol), the mixture was stirred at room temperature underan argon atmosphere for 4 h and the solvent was evaporated. The mixturewas partitioned between water and ethyl acetate, was extracted twicewith ethyl acetate, the organic extract was dried (potassium carbonate)and the solvent was removed in vacuo. Purification by flashchromatography, eluting with 25% ethyl acetate/hexanes, followed bytrituration of the product with ether/hexanes provided a white solid(0.125 g, 95%): m.p. 50°-53° C.

Analysis Calc. for C₁₉ H₂₄ N₂ O₃ : C 69.44, H 7.37, N 8.53; found: C69.35, H 7.47, N 8.28.

EXAMPLE 14 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one14a. 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-onedimethyl ketal

A mixture of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.5 g, 1.6mmol), triethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amountof p-toluenesulfonic acid in methanol (20 mL) was heated gently under anargon atmosphere for 2 h. The mixture was cooled, was partitionedbetween aqueous sodium carbonate and ethyl acetate, was extracted twicewith ethyl acetate, the organic extract was dried (potassium carbonate)and the solvent was removed in vacuo to provide an oil (0.57 g, 99%).

14b. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-onedimethyl ketal

A solution of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethylketal (0.57 g, 1.6 mmol) in toluene (20 mL) at room temperature under anargon atmosphere was treated with a solution of dissobutylaluminiumhydride (1.5M in toluene, 2.7 mL, 4 mmol). After 2 h, a solution ofsaturated aqueous sodium bisulfite was added and the mixture wasextracted twice with ethyl acetate. The organic extract was washed with5% aqueous sodium carbonate,was dried (potassium carbonate) and thesolvent was removed in vacuo to provide an oil (0.55 g, 96%).

14c. 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one

4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-formylcycohexan-1-one dimethylketal (0.1 g, 0.28 mmol) in ethyl acetate (2 mL) was treated with 3Nhydrochloric acid (5 mL) and the mixture was stirred vigorously andgently heated for 10 min. The mixture was extracted twice with ethylacetate, the combined organic extracts were washed with 5% aqueoussodium carbonate, dried (potassium carbonate) and the solvent wasremoved in vacuo. This material, combined with that obtained from anidentical reaction, was purified by flash chromatography, eluting with2% ethyl acetate/chloroform, to provide a white solid (0.1 g, 57%): m.p.55°-57° C.

Analysis Calc. for C₁₉ H₂₄ O₄ : C 72.13, H 7.65; found: C 72.09, H 7.57.

EXAMPLE 154(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one15a.4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one-dimethylketal

To a solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethylketal (0.24 g, 0.66 mmol) in 1,2-dimethyl-ethane (5 mL) under an argonatmosphere was added sodium borohydride (0.05 g, 1.3 mmol) and themixture was stirred at room temperature for 0.75 h. Water was added, themixture was partitioned between ether and water, was extracted twicewith ether, the organic extract was dried (potassium carbonate) andevaporated to an oil (0.19 g, 79%).

15b.4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one

4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)-cyclohexan-1-onedimethyl ketal (0.15 g, 0.41 mmol) in ether (2 mL) was treated with 1Nhydrochloric acid (2 mL) and the mixture was stirred vigorously andgently heated for 10 min. The mixture was extracted with ether, thecombined organic extracts were washed with 5% aqueous sodium carbonate,dried (potassium carbonate) and the solvent was removed in vacuo.Purification by flash chromatography, eluting with 25% ethylacetate/chloroform, provided a wax (0.06 g, 56%).

Analysis Calc. for C₁₉ H₂₆ O₄ : C 71.67, H 8.23; found: C 71.81, H 8.19.

EXAMPLE 164-(3-(Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one16a.4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethoxy)cyclohexan-1-onedimethyl ketal

A solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-onedimethyl ketal (0.37 g, 1.02 mmol) in methylene chloride (5 mL) wasadded dropwise to a solution of diethylaminosulfur trifluoride (0.14 mL,1.02 mmol) at -78° C. under an argon atmosphere. The mixture was allowedto warm to room temperature and after 0.75 h, 5aqueous sodium carbonatewas added. The mixture was extracted with chloroform, the organicextract was dried (magnesium sulfate) and the solvent was removed invacuo to provide a yellow oil (0.3 g, 80%).

16b.4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one

4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-onediethyl ketal (0.35 g, 0.95 mmol) in ethyl acetate (2 mL) was treatedwith 1N hydrochloric acid (2 mL) and the mixture was stirred vigorouslyand gently heated for 10 min. The mixture was extracted with ethylacetate, the organic extract was washed with 5% aqueous sodiumcarbonate, dried (magnesium sulfate) and the solvent was removed invacuo. Purification by flash chromatography, eluting with 25% ethylacetate/hexanes, followed by trituration with ether/hexanes, provided awhite solid (0.075 g, 24%): m.p. 72°-74° C.

Analysis Calc. for C₁₉ H₂₅ FO₃ : C 71.23, H 7.87; found: C 71.22, H7.70.

EXAMPLE 174-Aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one17a.4-Aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-onedimethyl ketal

A solution of4-cycano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethylketal (0.34 g, 0.95 mmol) and powdered potassium carbonate (0.7 g, 5.1mmol) in methanol (20 mL) and water (4 mL) at 0° C. was treated withhydrogen peroxide (30% solution, 2.55 mL). The mixture was allowed towarm to room temperature and, after seven days, brine was added and themixture was extracted with methylene chloride. The organic extract waswashed twice with brine, dried (potassium carbonate) and the solvent wasremoved in vacuo. Purification by flash chromatography provided theamide (0.055 g, 15% along with recovered starting material (0.25 g).

17b.4-Aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

A mixture of4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-onedimethyl ketal (0.055 g, 0.15 mmol) and p-toluenesulfonic acid(catalytic amount) in 20% aqueous acetone (5 mL) was stirred under anargon atmosphere at reflux for 8 h. The mixture was cooled, diluted withwater and extracted with methylene chloride. The organic extract wasdried (magnesium sulfate) and the solvent was removed in vacuo toprovide a hygroscopic, amorphous material (0.035 g, 72%).

Analysis Calc. for C₁₉ H₂₅ NO₄ 3/8 H₂ O: C 67.48, H 7.67, N 4.14; found:C 67.38, H 7.54, N 3.86.

EXAMPLE 184-(3-Cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one 18a.4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohex-1-one dimethylketal

To a solution of potassium t-butoxide (0.155 g, 1.38 mmol) in drytetrahydrofuran (5 mL) under an argon atmosphere at -78° C. was added asolution of dimethyl (diazomethyl)phosphonate (ca. 88% pure, 0.24 g,1.38 mmol). After 0.25 h, a solution of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one dimethylketal (0.42 g, 1.15 mmol) in dry tetrahydrofuran (5 mL) was addeddropwise and the mixture was allowed to stir at -78° C. under an argonatmosphere for 5 h. Aqueous acetic acid was added, the mixture wasconcentrated, partitioned between methylene chloride and water andextracted twice. The organic extract was dried (magnesium sulfate) andevaporated. Purification by flash chromatography, eluting with 3:1hexanes/ethyl acetate, provided an oil (0.13 g, 32%).

18b. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one

A mixture of4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one dimethylketal (0.13 g, 0.36 mmol) and p-toluenesulfonic acid (catalytic amount)in acetone (5 mL) was stirred under an argon atmosphere at roomtemperature for 1.5 h. The mixture was concentrated, diluted with ethylacetate and washed with water. The organic extract was dried (magnesiumsulfate) and the solvent was removed in vacuo to provide an oil (0.11 g,97%).

Analysis Calc. for C₂₀ H₂₄ O₃.1/2H₂ O: C 74.74, H 7.84; found: C 74.81,H 7.84.

EXAMPLE 19 4-(3,4-Bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one19a. 4-(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one dimethylketal

A mixture of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one(1.34 g, 4.05 mmol), trimethyl orthoformate (0.53 mL, 4.85 mmol) and acatalytic amount of p-toluenesulfonic acid in methanol (40 mL) washeated gently under an argon atmosphere for 2 h. The mixture was cooledand then concentrated. The residue was partitioned between 5% aqueoussodium carbonate and ethyl acetate, was extracted twice with ethylacetate, the organic extract was dried (potassium carbonate) and thesolvent was removed in vacuo to provide an oil (1.5 g, 98%).

19b. 4-(3,4-Bisdifluoromethoxyphenyl)-4-formylcyclohexan-1-one dimethylketal

A solution of 4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-onedimethyl ketal (1.5 g, 3.98 mmol) in toluene (50 mL) at room temperatureunder an argon atmosphere was treated with a solution ofdiisobutylaluminum hydride (1M in toluene, 10 mL, 10 mmol). After 4 h, asolution of saturated aqueous sodium bisulfite was added and the mixturewas extracted twice with ethyl acetate. The combined organic extract wasdried (potassium carbonate) and the solvent was removed in vacuo toprovide an oil (1.5 g, 99%).

19c. 4-(3,4-Bisdifluoromethoxy)-4-ethynylcyclohex-1-one dimethyl ketal

To a suspension of potassium t-butoxide (0.18 g, 1.6 mmol) in drytetrahydrofuran (5 mL) under an argon atmosphere at -78° C. was added asolution of dimethyl (diazomethyl)phosphonate (ca. 90% pure, 0.27 g, 1.6mmol) in tetrahydrofuran (5 mL). After 0.25 h, a solution of4-(3,4-bisdifluoromethoxyphenyl)-4-formylcyclohexan-1-one dimethyl ketal(0.5 g, 1.3 mmol) in dry tetrahydrofuran (5 mL) was added dropwise andthe mixture was allowed to stir at -78° C. under an argon atmosphere for10 min. Aqueous acetic acid was added, the mixture was concentrated andwas partitioned between methylene chloride and water. The organicextract was dried (magnesium sulfate)and evaporated. Purification byflash chromatography, eluting with 3:1 hexanes/ethyl acetate, providedan oil (0.2 g, 41%).

19d. 4-(3,4-Bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one

A mixture of 4-(3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohex-1-onedimethyl ketal (0.2 g, 0.53 mmol) and p-toluenesulfonic acid (catalyticamount) in acetone (10 mL) was stirred under an argon atmosphere at roomtemperature for 0.5 h. The mixture was concentrated, was diluted withmethylene chloride and was washed with water. The organic extract wasdried (magnesium sulfate) and the solvent was removed in vacuo toprovide an oil (0.17 g, 98%).

Analysis Calc. for C₁₆ H₁₄ F₄ O₃ : C 58.19, H 4.27; found: C 58.30, H4.40.

EXAMPLE 204-(3,4-Bisdifuloromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-one 20a.4-Aminomethyl-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethylketal

A solution of 4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-onedimethyl ketal (0.5 g, 1.33 mmol) in tetrahydrofuran (3 mL) at roomtemperature under an argon atmosphere was added to a suspension oflithium aluminum hydride (0.1 g, 2.66 mmol) in tetrahydrofuran (4.5 mL).After 6 h, ethyl acetate and saturated aqueous sodium potassium tartratewere added, followed by saturated aqueous sodium carbonate, and themixture was extracted four times with ethyl acetate. The organic extractwas dried (potassium carbonate) and the solvent was removed in vacuo toprovide an oil (0.43 g, 85%).

20b. 4-(3,4-Bisdifluoromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-one

To a solution of4-aminomethyl-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethylketal (0.43 g, 1.13 mmol) and triethylamine (0.16 mL, 1.13 mmol) inmethylene chloride (7 mL) under an argon atmosphere at -78° C. was addedmethyl oxalyl chloride (0.12 mL, 1.07 mmol). After 5 min. water wasadded and the mixture was partitioned between methylene chloride andacidic water and was extracted twice. The organic extract was dried(potassium carbonate) and evaporated to an oil (0.59 g). This oil is inmethanol (ca. 2 mL) in a pressure tube was cooled to -78° C. and anequal volume of anhydrous ammonia was condensed into the tube. The tubewas sealed, was allowed to come to room temperature and was stirredunder pressure for 6 h. The ammonia was allowed to evaporate, themixture was partitioned between chloroform and water and was extractedthree times. The organic extract was dried (potassium carbonate) andevaporated to the ketal, an oil (0.6 g). This oil in tetrahydrofuran (13mL) was treated with 5% hydrochloric acid (7.6 mL) and the mixture wasstirred under an argon atmosphere at room temperature for 20 h. Themixture was poured into acidic water, was extracted three times withmethylene chloride, the organic extract was dried (potassium carbonate)and the solvent was removed in vacuo. Purification by flashchromatography, eluting with 5% ether/chloroform, followed bytrituration with ether/methylene chloride, provided a white solid (0.21g, 45%): m.p. 164°-165° C.

Analysis Calc. for C₁₇ H₁₈ F₄ N₂ O₅ : C 50.25, H 4.47, N 6.89; found: C50.04, H 4.45, N 6.64.

EXAMPLE 214-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[2-(trimethylsilyl)ethoxycarbonyl)]cyclohexan-1-one

A solution of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one(0.18 g, 0.45 mmol) in 2-(trimethylsilyl)ethanol (1.0 mL) was heated at180° C. under an argon atmosphere for 2.5 h. The mixture was cooled, wasconcentrated and the product was purified by flash chromatography,eluting with 3:1 hexanes/ether, to provide a colorless oil (0.2 g, 95%).

EXAMPLE 224-Cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-one

A solution of4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.75 g,2.4 mmol) and concentrated hydrochloric acid (2 mL) in methanol (10 mL)was heated at reflux under an argon atmosphere for 2 h. The mixture wascooled, was diluted with water and was extracted three times withmethylene chloride. The organic extract was dried (magnesium sulfate)and was evaporated to the phenol (0.54 g, 92%). A vigorously stirredmixture of this phenol, 4-fluorobenzyl bromide (0.83 mL, 6.6 mmol) andpotassium carbonate (0.92 g, 6.6 mmol) in dimethylformamide (12 mL) washeated under an argon atmosphere at 90° C. for 2 h. The mixture wasallowed to cool, was diluted with water and was extracted three timeswith ether. The organic extract was dried (magnesium sulfate) and thesolvent was removed in vacuo. Purification by flash chromatography,eluting with 30% ethyl acetate/hexanes, provided a white solid (0.6 g,78%): m.p. 145°-146° C.

Analysis Calc. for C₂₁ H₂₀ FNO₃.1/5H₂ O: C 70.65, H 5.76, N 3.92; found:C 70.59, H 5.59, N 3.99.

EXAMPLE 234-Cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-oneoxime

A solution of4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl)cyclohexan-1-one(0.525 g, 1.49 mmol) and hydroxylamine hydrochloride (0.114 g, 1.63mmol) in pyridine (5 mL) was stirred at room temperature under an argonatmosphere for 18 h. The mixture was partitioned between 1 Nhydrochloric acid and methylene chloride, the organic extract was dried(magnesium sulfate) and the solvent was removed in vacuo. Purificationby flash chromatography, eluting with 35% ethylacetate/hexanes, provideda white solid (0.45 g, 82%): m.p. 55°-57° C.

EXAMPLE 244-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-4-ethynylcyclohexan-1-one

The title compound, prepared substantially as described above for4-(3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one in EXAMPLE19, was isolated as a solid: m.p. 75°-77° C.

Analysis Calc. for C₁₉ H₂₀ F₂ O₃ : C 68:25, H 6.03; found: C 67.93, H6.10.

EXAMPLE 254-Cyano-4-(3-cyclopropymethoxy-4-methoxyphenyl)cyclohexan-1-one oxime

The title compound, prepared substantially as described above for4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one oxime inEXAMPLE 13, was isolated as a solid: m.p. 75°-77° C.

Analysis Calc. for C₁₈ H₂₂ N₂ O₃.1/4 H₂ O: C 67.80, H 7.11, N 8.78;found: C 68.03, H 7.08, N 8.59.

EXAMPLE 262-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one26a.

2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

A solution of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one(1.0 g, 2.8 mmol) and sodium hydride (80% dispersion in mineral oil,0.09 g, 3.1 mmol) in dry hexamethylphosphoric triamide (8 mL) wasstirred under an argon atmosphere at room temperature for 0.5 h.Chloromethylmethyl ether (0.26 mL, 3.4 mmol) was added and stirring wascontinued for 4.5 h. The mixture was partitioned between ethyl acetateand saturated aqueous sodium bicarbonate, was extracted three times,theorganic layer was dried (sodium sulfate) and the solvent was removed invacuo. The product was purified by flash chromatography, eluting with3:1 hexanes/ethyl acetate, to provide a white solid (0.5 g, 44%): m.p.98°-99° C.

26b.2-Carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

A solution of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene(0.5 g, 1.25 mmol) and potassium hydroxide (0.21 g, 3.75 mmol) inmethanol (13 mL), tetrahydrofuran (5 mL) and water (7.5 mL) under anargon atmosphere was heated at 65° C. for 3 h. The mixture waspartitioned between methylene chloride and acidic water, was extractedtwice, the organic layer was dried (magnesium sulfate) and the solventwas removed in vacuo. Purification by flash chromatography, eluting with5% methanol/chloroform, provided an oil (0.26 g, 54%).

26c.2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

A mixture of2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene(0.26 g. 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) andisobutyl chloroformate (0.1 mL, 0.77 mmol) in dry 1,2-dimethoxyethane (7mL) was stirred under an argon atmosphere at room temperature for 10min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring wascontinued for 0.5 h. The mixture was partitioned between methylenechloride and 5% aqueous sodium carbonate, was extracted three times, theorganic layer was dried (potassium carbonate) and the solvent wasremoved in vacuo to provide a white solid (0.22 g, 85%): m.p. 120°-122°C.

26d.2-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one

A solution of2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene(0.22 g, 0.57 mmol) in 50% aqueous acetic acid (12 mL, containing 9drops concentrated sulfuric acid per 30 mL) was heated at 75° C. underan argon atmosphere for 2 h. The mixture was cooled, was partitionedbetween methylene chloride and water, was extracted twice, the organiclayer was dried (potassium carbonate)and the solvent was removed invacuo. Purification by flash chromatography, eluting with 5%methanol/chloroform, followed by crystallization from ether/methylenechloride, provided a white powder (0.07 g, 51%): m.p. 154°-155° C.

Analysis Calc. for C₁₉ H₂₂ N₂ O_(41/2H) ₂ O: C 64.94, H 6.60, N 7.97;found: C 64.93, H 6.56, N 7.61.

EXAMPLE 272-Carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one27a.4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[2-(trimethylsilyl)ethoxycarbonyl)]cyclohexan-1-one

A solution of2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one(0.18 g, 0.45 mmol) in 2-(trimethylsilyl)ethanol (1.0 mL) was heated at180° C. under an argon atmosphere for 2.5 h. The mixture was cooled, wasconcentrated and the product was purified by flash chromatography,eluting with 3:1 hexanes/ether, to provide a colorless oil (0.2 g, 95%).

27b.2-Carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one

A solution of4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[2-(trimethylsilyl)ethoxycarbonyl)]cyclohexan-1-one(0.2 g, 0.42 mmol) and tetrabutylammonium fluoride (1M solution intetrahydrofuran, 2 mL, 2 mmol) was stirred at room temperature under anargon atmosphere for 2.5 h. The mixture was poured into cold diluteaqueous hydrochloric acid, was extracted twice with ether, the organicextract was washed three times with ice water, was dried (sodiumsulfate) and the solvent was removed in vacuo. Trituration of theresidue provided a white powder (0.12 g, 77%): m.p. 110°-112° C. (dec.).

Analysis Calc. for C₁₉ H₁₉ F₂ NO₅ : C 60.16, H 5.05, N 3.69; found: C60.25, H 5.07, N 3.57.

EXAMPLE 284-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2,4-dicyanocyclohexan-1-one

To a stirred solution of1-amino-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl])-2,4-dicyanocyclohex-1-ene(0.25 g, 0.696 mmol) in ethanol (2 mL) was added 6N hydrochloric acid(0.6 mL) and the mixture was stirred for 1.5 h at ambient temperature.The reaction was poured into ice water, was extracted three times withether and the combined organic phase was washed with water, brine andwas dried (sodium sulfate). The solvent was evaporated and the residuewas purified by flash chromatography, eluting with 4% methanol/toluene,and the residue was triturated with ether to provide a white powder(0.08 g, 32%): m.p. 142°-143° C.

Analysis Calc. for C₁₉ H₁₈ F₂ N₂ O₃ 1/4 H₂ O: C 62.55, H 5.11, N 7.68;found: C 62.69, 62.39, H: 5.05, 5.04, N 7.47, 7.43.

EXAMPLE 292-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-29a.2-Carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

The title compound, prepared substantially as described above for2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-enein EXAMPLE 26a, was triturated with ether to provide white crystals(0.334 g, 77%): m.p. 81°-82° C.

Analysis Calc. for C₂₂ H₂₅ F₂ NO₆ : C 60.41, H 5.76, N 3.20; found: C60.32, H 5.80, N 3.21.

29b.2-Carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

The title compound, prepared substantially as described above for2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-enein Example 26b, was isolated as an oil.

29c.2-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene

The title compound, prepared substantially as described above for2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-enein EXAMPLE 26c, was isolated as an oil.

29d.2-Aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one

The title compound, prepared substantially as described above for2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-onein EXAMPLE 26d, was isolated as a white powder (0.025 g, 24%): m.p.157°-159° C.

Analysis Calc. for C₁₉ H₂₀ F₂ N₂ O₄.1/2H₂ O: C 58.91, H 5.46, N 7.23;found: C 58.86, H 5.32, N 6.95.

METHODS OF TREATMENT

In order to use a compound of Formula (I) or (II) or a pharmaceuticallyacceptable salt therefor the treatment of humans and other mammals, itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

The compounds of Formula (I) or (II), a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for theprophylatic or therapeutic treatment of any disease state in a human orother mammal which is mediated by inhibition of PDE IV, such as but notlimited to asthma, allergic, or inflammatory diseases. The compounds ofFormula (I) or (II) are administered in an amount sufficient treat sucha disease in a human or other mammal.

For the purposes herein all methods of treatment and dosage regimensapply equally to both the compounds of Formula (I) or (II).

In order to use a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals,it is normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

The amount of a compound of Formula (I) or (II) required for therapeuticeffect on topical administration will, of course, vary with the compoundchosen, the nature and severity of the condition and the animalundergoing treatment, and is ultimately at the discretion of thephysician.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/g to 40 mg/Kg, of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit activity.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

UTILITY EXAMPLES EXAMPLE A Inhibitory effect of Compounds of Formula (I)or (II) on in vitro TNF production by human monocytes

The inhibitory effect of compounds of Formula (I) or (II) on in vitroTNF production by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

EXAMPLE B

Two models of endotoxic shock have been utilized to determine n vivo TNFactivity for the compounds of Formula (I) or (II). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) or (II) can be determined using a battery offive distinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheat; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques [Torphy andCieslinski, Mol. Pharmacol. 37:206-214, 1990]. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol. 37:26-214, 1990. Positive IC₅₀ 'sin the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) or (II) have been demonstrated.

EXAMPLE D

The ability of selected PDE IV inhibitors to increase cAMP accumulationin intact tissues is assessed using U-937 cells, a human monocyte cellline that has been shown to contain a large amount of PDE IV. To assessthe activity of PDE IV inhibition in intact cells, nondifferentiatedU-937 cells (approximately 10⁵ cells/ reaction tube) were incubated withvarious concentrations (0.01-1000 μM) of PDE inhibitors for one minuteand 1 μM prostaglandin E2 for an additional four minutes. Five minutesafter initiating the reaction, cells were lysed by the addition of 17.5%perchloric acid, the pH was neutralized by the addition of 1M potassiumcarbonate and cAMP content was assessed by RIA. A general protocol forthis assay is described in Brooker et al., Radioimmunassay of cyclic AMPand cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Thecompounds of the working examples as described herein for Formula (I) or(II) have demonstrated a positive EC₅₉ s in the μM range in the aboveassay.

What is claimed is:
 1. A compound selected from the group consistingof4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one;4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one;4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one;4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one oxime;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-one;4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethylketal; 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-formylcyclohexan-1-onedimethyl ketal;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)cyclohexan-1-one-dimethylketal;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-one;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(fluoromethyl)cyclohexan-1-onedimethyl ketal;4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;4-aminocarbonyl-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-onedimethyl ketal;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one;4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohex-1-one dimethylketal; 4-(3,4-bisdifluoromethoxyphenyl)-4-ethynylcyclohexan-1-one;4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one dimethyl ketal;4-(3,4-bisdifuloromethoxyphenyl)-4-formylcyclohexan-1-one dimethylketal; 4-(3,4-bisdifluoromethoxy)-4-ethynylcyclohex-1-one dimethylketal;4-(3,4-bisdifluoromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-one;4-aminomethyl-4-(3,4-bisdifluoromethoxyphenyl)cyclohexan-1-one dimethylketal;4-(3,4-bisdifuloromethoxyphenyl)-4-(oxamidomethyl)cyclohexan-1-onedimethyl ketal;4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-one;4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl]cyclohexan-1-oneoxime;4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-4-ethynylcyclohexan-1-one;or 4-cyano-4-(3-cyclopropmethoxy-4-methoxyphenyl)cyclohexan-1-one oxime.2. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 3. A method for treating anallergic or inflammatory disease which method comprises administering toa subject in need thereof an effective amount of a compound of claim 1alone or in combination with a pharmaceutically acceptable excipient. 4.A compound selected form the group consistingof2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one;4-(3,4-bisdifluoromethoxyphenyl)-2-carbomethoxy-4-cyanocyclohexan-1-one;2-carbomethoxy-4-cyano-4-(3-difluoromethoxy-4-methoxyphenyl)cyclohexan-1-one;2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one;2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-one;4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-[2-(trimethylsilyl)ethoxycarbonyl)]-cyclohexan-1-one;2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2,4-dicyanocyclohexan-1-one;or2-aminocarbonyl-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one.5. A pharmaceutical composition comprising a compound of claim 4 and apharmaceutically acceptable excipient.
 6. A method for treating anallergic or inflammatory disease which method comprises administering toa subject in need thereof an effective amount of a compound of claim 4alone or in combination with a pharmaceutically acceptable excipient.